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SAN FRANCISCO—At the University of California, San Francisco (UCSF), an experiment conceived to explore the role of intestinal adult stem cells in wound healing has instead uncovered a new mechanism by which the intestinal lining recovers from injury by reactivating the expression of a fetal gene program. The finding sheds new insight into the process of tissue regeneration and the body’s natural healing abilities in response to internal injuries.
The experiment originally set out to explore the role of adult stem cells in wound healing. The lead authors were Ysbrand Nusse, a graduate student in the laboratory of UCSF’s Dr. Ophir Klein, and Dr. Adam K. Savage, a postdoctoral researcher in the lab of UCSF gut immunologist Dr. Richard Locksley. Klein, who is the Larry L. Hillblom Distinguished Professor in Craniofacial Anomalies and the Charles J. Epstein Professor of Human Genetics, and Locksley, the Marion and Herbert Sandler Distinguished Professor in Asthma Research and a Howard Hughes Medical Institute investigator, both served as senior corresponding authors on the paper.
For their experiment, the research team used mice infected with a parasitic nematode common in wild mice: Heligmosomoides polygyrus, whose larvae burrow into intestinal lining and causing tissue damage.
The researchers chose to examine a parasitic injury in order to simulate the kinds of internal tissue damage the animals would experience in the wild.
“The parasite used is a natural infection of mice in the wild,” say Locksley and Klein in a collective statement. “Studying mechanisms of repair that occur under natural conditions may be more revealing of normal responses as compared to more artificial conditions of injury, such as surgery or irradiation, that the animal has not evolved to handle.”
Stem cells present in the intestines help to regulate and replenish the epithelial cells that absorb nutrients and line the gut with protective mucus. The team hypothesized that these stem cells would increase their activity in response to the damage caused by the parasites, to begin healing the internal injuries.
Instead, to their initial bewilderment, signs of stem cell activity in the surrounding tissue disappeared altogether. Deepening the mystery, the wounded tissue began regenerating faster, even with no signs of stem cell gene expression in the injured area. It wasn’t until the team noticed the expression of a protein called Sca-1—a gene expressed during fetal development of the mouse’s gut—that they were able to start making sense of the results.
Their paper, published online in Nature on June 27, 2018, explained their findings.
“The paper focuses on demonstrating that an epithelial cell population in the injured area re-expresses a gene program that has previously been associated with the gene program expressed by fetal intestine during development,” Locksley and Klein report.
The results of the experiment suggest the re-activation of a “fetal program” of the cells—in which undifferentiated cells are produced quickly—in response to tissue damage. In this way, new cells grow quickly to repair damaged tissue, but do not differentiate into specialized functions. This leads to the rapid growths of undifferentiated cells to heal the wounds, without the markers of adult stem cell activity or the resultant specialized, differentiated types of functional cells.
“The ‘fetal program’ consists of genes expressed during development of the organism as the embryo develops in the mouse uterus; the ‘adult program’ consists of genes expressed during life after birth,” Locksley and Klein explain. “In general, fetal development is concerned with building tissues and organs, whereas adult life is concerned with functions of tissues and organs.
“For example, as a fetus, it is important to build a tongue, but it is not until after you are born, when you begin to eat and drink, that you need to taste anything.”
Curious to explore whether the re-activation of the “fetal program” response was specific to the parasitic infection, or a more general response to gut tissue damage, the team conducted follow-up experiments that examined the cells’ response to other forms of gut injury. In their follow-up experiments, the researchers once again observed a rapid proliferation of undifferentiated tissue in the absence of observable stem cell expression.
“The research suggests that similar programs might be activated in other tissues after injury,” say Locksley and Klein.
Indeed, the UCSF team’s findings add to a body of research exploring the link between parasitic injury and enhanced wound healing. A line of research led by Dr. Michael Smout and Prof. Alex Loukas at James Cook University (JCU) in Australia has been exploring a molecule called granulin found in the saliva of another parasitic worm, Opisthorchis viverrini, which appears to trigger prolific cell growth in order to sustain itself inside the liver of its victims. Unfortunately, this rampant cell growth caused by O. viverrini infections result in cholangiocarcinoma, a form of cancer in the liver and bile-duct. The JCU team hypothesize, however, that understanding and harnessing the growth factor in a controlled setting could have medical uses in treating diabetic ulcers and other diseases associated with non-healing wounds.
There is much early research left to be done before these processes can be fully understood and replicated in the clinic, but the implications for the future of medicine are far-reaching.
“It provides a model system to start on the next steps, which are to identify the signal(s) that cause the re-appearance of the fetal gene program,” Locksley and Klein remark. “Having such signals might allow activating the program in controlled ways in periods when it might be more important to ‘build’ tissue than to worry too much about whether it is functioning—for example, skin after a bad burn.”